The long-term objectives of this research plan are to investigate at the cellular, biochemical, molecular and clinical levels five specific areas of current importance related to hormones that affect mineral ion homeostasis. Studies will focus on: 1. The newly discovered parathyroid hormone-related protein (PTHrP), its causative role in cancer hypercalcemia syndromes, its functions in non-neoplastic cells and in normal physiology, and its mechanism of action; 2. Mechanistic studies on parathyroid hormone action on osteoblasts, including functional roles of the cAMP and inositol lipid/Ca2+ transduction systems and characterization of the osteoblast-derived stimulator of osteoclastic bone resorption; 3. Direct actions of estrogens on human osteoblasts; 4. Novel actions of vitamin D (1,25(OH)2D3) on nonclassical target cells including regulation of calcium homeostasis and function in pituitary cells and keratinocytes; and 5. Cell biology and clinical studies on calcitonin with emphasis on the mechanism of action on osteoclasts, regulation of calcitonin secretion by extracellular Ca2+, and investigations on the very early diagnosis and genetic cause of hereditary medullary thyroid carcinoma (the MEN-2 syndromes). The experiments proposed are designed to investigate several fundamental aspects of hormones affecting mineral metabolism and to relate these findings to clinically important disorders of bone metabolism in the human including osteoporosis, hyperparathyroidism, pheochromocytoma, and the hypercalcemia of cancer.